The stress response engendered by negative valence stimuli has been implicated across psychiatric disorders and varies in the healthy population. This study (an RO3 in response to RFA PAR-14-008) seeks to understand the neurobiologic mechanisms underlying the negative valence domain by identifying its biosignature1 (specifically here, underlying genes, circuits, physiology, and symptomatology) associated with immune pathway dysregulation. Our prior studies suggest that stress responses in the negative valence domain have fetal origins, and thus we believe that its biosignature associated with immune dysregulation will be identifiable both prenatally and in adulthood. We and others demonstrated at the human and animal levels that the fetal programming of stress response circuitry development (i.e., anterior hypothalamus (aHYPO), amygdala (AMYG), hippocampus (HIPP), medial prefrontal and anterior cingulate cortices (mPFC, ACC), and periaqueductal gray (PAG)9-13) is critical to understand adult stress response circuitry deficits, steroid hormone and autonomic nervous system (ANS) dysregulation in specific diagnoses in humans7,8,14-16 and associated mood- and anxiety-related behaviors in animals17-20. In this RO3, we will relate this adult phenotyping to prenatal exposures and polygenic risk for psychopathology. The sample will consist of 102 subjects, equally divided by sex (a community-population mix of healthy and ill individuals) from a unique prenatal cohort (followed to age ~50) in which biosamples indicating maternal immune responses to stress at mid-gestation have been evaluated in NIMH RO1 MH56956 (psychoses/healthy controls) and P50MH082679 (depression/healthy controls). As adults, they completed fMRI using a visual stress challenge to negative valence stimuli in tandem with in-scanner electrocardiogram, hormone evaluations, and symptomatology. Further, we will genotype (GWAS) these individuals and assign a polygenic risk score based on psychoses and major depressive disorder from the Psychiatric Genetics Consortium findings26. Thus, we will begin to: 1) characterize immune components of the adult biosignature of the negative valence domain as it relates to brain circuitry activation, physiology, and symptomatology; and 2) identify prenatal immune biomarkers and polygenic risk associated with this adult biosignature. In so doing, we will provide critical information for the validation of this domain as a core component of psychopathology that crosses diagnostic categories, varies within the healthy population, and can be used as functional targets for immune-related therapeutics.